Sequential production of fatty liver, hepatitis, and cirrhosis in sub-human primates fed ethanol with adequate diets.

Abstract

This study reproduces in experimental animals the sequential development of all the liver lesions seen in the human alcoholic: in 15 baboons fed ethanol, all developed fatty liver, five progressed to hepatitis, and five had cirrhosis. Maintenance of a nutritionally adequate regimen despite the intake of inebriating amounts of ethanol (50% of total calories) was achieved by incorpora.tion of the ethanol in a totally liquid diet. Upon ethanol withdrawal, signs of physical dependence, such as seizures and tremors, developed. Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis) and differed from the alterations produced by choline and protein deficiencies. At the fatty liver stage, some "adaptive" increases in activity of microsomal enzymes [aniline hydroxylase (EC 1.14.14.1) and the microsomal ethanol oxidizing system] were observed, but these tendedto disappear with the development of hepatitis and cirrhosis. Fat accumulation was also much more pronounced in the animals with the hepatitis as compared with those with simple fatty liver (an 18-fold compared with 3-to 4-fold increase in liver triglycerides). The demonstration that these lesions can develop despite an adequate diet indicates that in addition to correction of the nutritional status, control of alcohol intake is mandatory for the management of patients with alcoholic liver injury.

Gene Expression Profiling of Alcoholic Liver Disease in the Baboon (Papio hamadryas) and Human Liver

“…Genes up-regulated specifically in the baboon from the cytochrome P450 gene family involved in xenobiotic metabolism were CYP2E1, CYP1A1, CYP3A, [3][4][5][6][7] CYP4A11, CYP4B1, CYP4F2, CYP7A1, CYP17A1, and CYP27A (Table 3). In human, CYP1B1, CYP2A6, and CYP3A7 were up-regulated and CYP2E1 and cytochrome P450-aromatic compound-inducible were downregulated.…”

“…Animals were fed the LieberDeCarli diet, a nutritionally adequate liquid diet in which the control and ethanol animals are fed isocaloric diets in which dextrose is substituted for ethanol as described. 6 Needle liver biopsies were obtained from alcohol-fed animals and relevant pair-fed controls (two biopsies from each animal). The histopathology of the biopsies showed cirrhosis, steatosis, and inflammation of the tissue as previously reported 6 and illustrated in Figure 1.…”

“…6 Needle liver biopsies were obtained from alcohol-fed animals and relevant pair-fed controls (two biopsies from each animal). The histopathology of the biopsies showed cirrhosis, steatosis, and inflammation of the tissue as previously reported 6 and illustrated in Figure 1. The biopsies were snap-frozen, and stored in liquid N 2 until extraction of RNA was performed.…”

“…Of the various animal models of ALD, the baboon model has been shown to reproduce sequential development of all of the liver lesions observed in human alcoholics without exposure to other hepatotoxins. 6 For this study, the pathogenesis of ALD was studied in the baboon model by comparing intrahepatic gene expression of alcohol-fed and control baboons using cDNA array analysis. The studies were extended to human ALD by comparison of gene expression profiles in nondiseased and cirrhotic liver tissue.…”

Mitochondrial alterations in livers of Sod1−/− mice fed alcohol

“…Mitochondrial GSH was depleted by an ethanol-induced impairment in mitochondrial GSH transport, due to decreased membrane fluidity (12). Patients and baboons with alcoholic hepatitis displayed mitochondria with morphological aberrations (13)(14)(15). While the role of oxidative stress in alcohol-induced cell injury is well documented (16), what alterations occur in mitochondria in in vivo models with alcohol-induced liver injury are still uncertain.…”